Abstract: Hypoglycemia is the most prevalent clinical complication in the daily management of diabetes and is the major obstacle to normalizing blood sugar. For people with Type 1 diabetes (T1DM), hypoglycemia associated autonomic failure (HAAF) increases the risk for severe hypoglycemia by a factor of 25 or more. A major component of HAAF is hypoglycemia unawareness, which involves in the loss/diminution of warning symptoms to hypoglycemia that would normally prompt a corrective behavioral response (e.g., eating food). With a goal of identifying existing biological compounds that could restore hypoglycemia awareness (ie, repurpose existing FDA- approved drugs), our laboratory recently completed a drug screen using a novel animal model of hypoglycemia unawareness in which preconditioned rats failed to increase food consumption in response to an episode of insulin induced hypoglycemia. Of all drugs tested, the dopamine antagonist metoclopramide consistently restored hypoglycemia awareness in several of our animal models tested. The goal of Aim 1 in the proposed grant is to validate in T1DM animal models of HAAF whether leading drugs identified in our recent drug screen restore both, 1) hypoglycemia awareness, and 2) the impaired sympathoadrenal response to hypoglycemia. Utilizing the gold standard hyperinsulinemic hypoglycemic clamp technique, drug validation studies are proposed in two independent T1DM rodent models of HAAF (both hypoglycemia unaware rats as well rats with recurrent hypoglycemia-induced sympathoadrenal deficiency) to determine if treatment with our leading drugs reverse these two principal pathologic components of HAAF. In Aim 2, a clinical trial is proposed to test whether the lead compound identified in our drug screen can restore both hypoglycemia awareness and the counterregulatory response to hypoglycemia in subjects with T1DM and HAAF. A placebo controlled, randomized trial will test whether four weeks of treatment with metoclopramide (our lead drug noted to particularly efficacious in several preclinical models) will, 1) reduce the incidence of hypoglycemia, 2) improve hypoglycemia symptom recognition, and 3) improve the sympathoadrenal response to hypoglycemia. Indices of improvement will be assessed, 1) in the outpatient setting with hypoglycemia event diaries, hypoglycemia awareness questionnaires, and continuous glucose monitors, and 2) in the laboratory setting with stepped hypoglycemic clamps which quantifies measurements of symptomatic awareness and counterregulatory hormone responses. By proceeding forward with the novel results from our recent drug screen, the proposed studies are the logical next step in seeking to repurpose existing FDA approved drugs to treat hypoglycemia associated autonomic failure in people with Type 1 diabetes.